This invention relates to the use of combinations of trastuzumab with an mTOR inhibitor and/or a HKI-272, for the treatment of neoplasms associated with overexpression or amplification of HER2.
CCI-779, rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid, is an ester of rapamycin which has demonstrated significant inhibitory effects on tumor growth in both in vitro and in vivo models. This compound is now known generically under the name temsirolimus. The preparation and use of hydroxyesters of rapamycin, including temsirolimus, are described in U.S. Pat. Nos. 5,362,718 and 6,277,983.
Temsirolimus exhibits cytostatic, as opposed to cytotoxic properties, and may delay the time to progression of tumors or time to tumor recurrence. Temsirolimus is considered to have a mechanism of action that is similar to that of sirolimus (rapamycin). Temsirolimus binds to and forms a complex with the cytoplasmic protein FKBP, which inhibits an enzyme, mTOR (mammalian target of rapamycin, also known as FKBP12-rapamycin associated protein [FRAP]). Inhibition of mTOR's kinase activity inhibits a variety of signal transduction pathways, including cytokine-stimulated cell proliferation, translation of mRNAs for several key proteins that regulate the G1 phase of the cell cycle, and IL-2-induced transcription, leading to inhibition of progression of the cell cycle from G1 to S. The mechanism of action of temsirolimus that results in the G1-S phase block is novel for an anticancer drug.
Metastatic breast cancer (MBC) is essentially incurable with standard therapy, and patients with MBC have a median survival of about 2 years after documentation of metastasis. As a consequence, the goals of treatment are to improve patients' symptoms while trying to maintain (or improve, in certain cases) quality of life. Prolonging survival remains a clear goal, particularly in breast cancer that has overexpression or amplification of the her-2 oncogene.
Herceptin® trastuzumab is an FDA-approved therapeutic monoclonal antibody for HER2 protein overexpressing metastatic breast cancer. A murine monoclonal antibody was described [see, U.S. Pat. No. 5,705,151]. The murine MAb4D5 molecule described in that document has been humanized in an attempt to improve its clinical efficacy by reducing immunogenicity and allowing it to support human effector functions. WO 92/22653. Later documents describe the development of a lyophilized formulation comprising full length humanized antibody huMAb4D5-8 described in WO 92/22653. Herceptin® trastuzumab is currently approved by the FDA for the treatment of metastatic breast cancer that overexpresses HER2—(1) as a single agent after previous treatment of the metastatic breast cancer with one or more chemotherapy regimens and (2) in combination with paclitaxel in such patients without prior chemotherapy for their metastatic breast cancer. Moreover, there is evidence that the addition of trastuzumab to taxane adjuvant or neoadjuvant chemotherapy improves to patients with earlier stage breast cancer.
HKI-272, (E)-N-{4-[3-chloro-4-(2-pyridinyl methoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide, has been described as a promising anticancer drug candidate for the treatment of breast cancers and other HER-2-dependent cancers. Because it also inhibits the EGFR kinase with similar potency, HKI-272 may be useful to treat tumors that overexpress both HER-2 and EGFR and be more efficacious than a specific EGFR or HER-2 antagonist. S. K. Rabindran et al, “Antitumor Activity of HKI-272, an Orally Active, Irreversible Inhibitor of the HER-2 Tyrosine Kinase”, Cancer Research 64, 3958-3965, Jun. 1, 2004. See, U.S. Pat. No. 6,288,082; 6,297,258.
What is needed is an improved antineoplastic therapy.